Heart diseases such as myocardial infarction, cardiomypathy, arrhythmia, heart failure and the like are one of three major causes for death in Japan, generating a significant problem in medical care. Conventionally, drugs such as a diuretic, β-blocker, ACE inhibitor, calcium antagonist and the like are used for treatment of heart diseases, however, these drugs do not radically treat heart diseases.
CD9 is a membrane protein having a molecular weight of 27 kDa classified into one of transmembrane 4-times type protein super family (TM4SF) . Regarding the action of CD9 in an organism, there are reports that it is a cell-specific marker derived from pre B (Masellis-Smith A et al; J Immunol. 144 15, 1607-1613, 1990), that it expresses in various cells irrespective of hematopoietic cells or non-hematopoietic cells (Maecker H. T et al.; FASEB J. 11, 428-442, 1997, Berditchevski F; J Cell Sci. 114, 4143-4151, 2001), that it relates to aggregation and differentiation of pre B cells (Masellis-Smith A et al; J Immunol. 144, 1607-1613, 1990), that it relates to activation of platelets (Jennings L K et al.; J Biol Chem. 265, 3815-3822, 1990), that it relates to survival and adhesion of various cells typically including cancer cells (Hashida H, et al.: Br J Cancer., 89: 158-67, 2003) , that it is a membrane protein indispensable for fertilization (Miyado K et al. ; Science 287, 321-324, 2000), that it causes association of a plurality of proteins in a cell membrane, acts as a molecule for coordinating and promoting a mutual action between proteins, and relates to phenomena of injury healing such as cell adhesion, proliferation, differentiation, immune, hemostatis and the like (Berditchevski F; J Cell Sci. 114, 4143-4151, 2001, Klein-Soyer C et al; Arterioscler Thromb Vasc Biol. 20, 360-3).
On the other hand, there is also a report regarding a relation between CD9 and HB-EGF (heparin binding epidermal growth factor). For example, there are reports on formation of a complex with HB-EGF or integrin α3β1 (Nakamura Y, et al: J Histochem Cytochem 49: 439-444, 2001), regulation of an activity as a juxtacrine factor of proHB-EGF as a precursor of HB-EGF (Higashiyama S., et al, : J. Cell Biol. 128, 929-938.1995, Iwamoto R, Mekada E: Cytokine & Growth Factor Reviews. 11: 335-344, 2000), and possibility of representation of variety of an activity of HB-EGF by relating to a process of processing of HB-EGF (Nakagawa T et al; J Biol Chem. 271, 30858-30863, 1996, Nakamura K et al; J Biol Chem. 275, 18284-18290, 2000). There are also reports that kidney epithelial cells also are improved in survival by co-expression of HB-EGF and CD9 in an ischemic disorder model (Takamura T et al; Kidney Int. 55, 71-81, 1999), that, in a process of arteriosclerosis, HB-EGF is expressed in normal aorta (Miyagawa J et al; J Clin Invest. 95, 404-411, 1995) and coronary (Nakata A et al; Circulation 94, 2778-2786, 1996), on the other and, CD9 expresses in arteriosclerosis lesion and some inner membrane smooth muscle cells, and co-expression of CD-9 and proHB-EGF promotes proliferation of smooth muscle cells by proHB-EGF (Nishida M et al; Arterioscler Thromb Vasc Biol. 20, 1236-1243, 2000), thus, CD9 is possibly an important molecule for regulating an activity of HB-GF assisting a balance of proliferation and transformation of fibroblasts in a process of arteriosclerosis and tissue repair (Kirkland G et al; J Am Soc Nephrol. 9, 1464-73, 1998). Further, the present inventors have a finding that excess expression of HB-EGF in a myocardial infarction model animal promotes compensatory hypertrophy of a myocardial cell, while promotes proliferation of myofibroblasts and enhances fibering, thereby, promoting decrease in a cardiac function, that is, HB-EGF is a central factor playing an important role in progressing of pathology.
As described above, there are a lot of reports on the action of CD9 and a relation of CD9 and HB-EGF, however, there is no report on a fact that CD9 suppresses cardiac hypertrophy, or suppresses tachycardia.